Reagent useful for cleaving a protected functional group

ABSTRACT

The subject matter of the present invention relates to a reagent and a process useful for cleaving a functional group protected by an alkoxycarbonyl group during an organic synthesis. This reagent comprises: a) an aqueous phase; b) a catalyst comprising at least one group VIII element in the periodic table of elements and at least one water-soluble ligand, wherein the group VIII element in the periodic table is maintained in the aqueous phase by the formation of a complex with at least one water-soluble ligand; and c) a nucleophilic compound soluble in the aqueous phase; and optionally d) an organic phase.

This application is a division of Ser. No. 08/107,903 filed Aug. 18,1993, U.S. Pat. No. 5,847,117 which is a continuation of Ser. No.08/046,318 filed Apr. 15, 1993, abandoned.

The subject matter of the present invention relates to a reagent and aprocess useful for cleaving a functional group protected by analkoxy-carbonyl group during an organic synthesis. It relates moreparticularly to the cleavage of an alkoxy-carbonyl group from afunctional group, wherein the alkoxyl group has an unsaturation in the βposition, such as propargyl or allyl groups.

It is common to protect a molecule by blocking the functional groupswith so-called protecting groups because, under certain operatingconditions, the functional groups might be reactive or considered assuch.

These techniques are particularly useful during peptide synthesiswherein the functional groups most commonly protected are acid, alcohol,amine and thiol functional groups.

Examples of protecting groups most commonly used include the BOC ortert-butyloxycarbonyl group, the Z or benzyloxyl group, and even theFMOC group. It should be pointed out that protecting groups which havean allyl structure would have been considered as potentially veryvaluable if suitable cleavage means were available.

The deprotection or removal of the protecting group routinely used is alysis in acidic medium, in general in an anhydrous halohydric mediumwith a water content generally less than 1%, preferably less than 10⁻³,most preferably less than 10⁻⁴.

However, this technique has many disadvantages. The cleavage reaction issometimes slow or requires a large excess of reagent. The alkoxyl groupsalso have a tendency to be converted to a carbocation, progressingtowards double bonds when possible or towards alkylation reactions onthe ring, which is particularly troublesome in the case of the synthesesof peptides whose sequence contains nucleophilic residues such asaromatic rings (e.g., tryptophan, tyrosine, phenylalanine and the like)or sulfur-containing rings (e.g., methionine). They can even alkylatethe functional groups being released.

The above-described technique is either not selective or gives poorresults in the case of alkoxycarbonyl groups having an unsaturation inthe β position.

This is the reason why it has been proposed to carry out the cleavage ofthe alkoxycarbonyl functional groups having the characteristics above byusing elements from Group VIII of the Periodic Table and generallyforming a complex with various ligands.

However, although slightly facilitating a cleavage, this technique hasthe same disadvantages as those described earlier, including thealkylation of the nucleophilic functional groups present in the moleculesynthesized.

Accordingly, one of the objects of the present invention is to provide aprocess and a reagent which substantially accelerate the cleavagekinetics.

Another object of the present invention is to provide a process and areagent which avoid the reactions for alkylating the aromatic rings.

Another object of the present invention is to provide a process and areagent which avoid the reactions for alkylating the so-callednucleophilic functional groups.

These objects and others, which will become apparent in the followingtext, are achieved by means of a reagent which is useful for cleavingunsaturated alkyloxycarbonyl functional groups.

This cleavage, which occurs between the alkyl group and the carbonylfunctional group (--CO--), may result in other bonds being ruptured,thus completing the release of certain functional groups. In the presentdescription, alk-yl is taken in its etymological sense of being thehydrocarbon residue of an alk-ohol, ignoring the alcohol (or "ol")functional group.

The reagent according to the present invention comprises:

a) an aqueous phase;

b) a catalyst comprising at least one Group VIII element in the periodictable of elements and at least one water-soluble ligand, wherein theGroup VIII element in the periodic table is maintained in the aqueousphase by the formation of a complex with at least one water-solubleligand; and

c) a nucleophilic compound soluble in the aqueous phase.

When the substrate and/or the end product are sparingly soluble in theaqueous phase, it is possible to carry out the reaction by usingsolvents A and/or B.

Solvents A are organic solvents which dissolve at least 1%, preferablyat least 2%, most preferably 5% by weight of the substrate and aresufficiently hydrophobic such that the solvents do not mix with water inall proportions.

Solvents A can also be used to create a biphasic medium which enhancesthe selectivity of the protected functional groups.

It is preferable that the water should dissolve at most only 10% ofsolvent A, advantageously at most 1% by weight. This would be the caseeven when the substrate acts as another solvent.

It is preferable that solvent A should dissolve at most only 10% ofwater, advantageously at most 1% by weight. Again, this would be thecase even when the substrate acts as another solvent.

Solvents A may be mixtures, including crude oil fractions. Naturally,under the operating conditions of the present invention, solvent A mustbe inert towards the substrates and the reagents used.

The preferred solvent families include hydrocarbons, aromaticderivatives, ethers, esters and halogenated solvents. In order torecover these solvents, it is desirable for the solvents to be lessnucleophilic than the nucleophilic compounds to avoid interference withthe reaction, unless the nucleophilic compound is in sufficient excessto be able to act as a solvent.

Specific examples of the above solvent include dichloromethane,1,2-dichloroethane, 1,1,1-trichloroethane as halogenated aliphaticderivatives; toluene as aromatic derivatives; chlorobenzene ashalogenated aromatic derivatives; ethyl acetate and isopropyl acetate asesters; tert-butyl and methyl ether as ethers; as well as anisole andheavy alcohols, which satisfy the criteria of immiscibility as specifiedabove.

For reasons of industrial economy, it is preferable that solvent A isdistillable at atmospheric pressure or under a low or secondary vacuum.

Among solvents A, there should be mentioned in particular those whichare phenolic and which are described in detail in French application No.89/15957, which corresponds to U.S. Ser. No. 07/621,468 filed on Dec. 4,1990, and French application No. 91/12524, which corresponds to U.S.Ser. No. 07/958,758 filed on Oct. 9, 1992, which are hereby incorporatedby reference.

According to one embodiment of the present invention, when thesubstrates are not water soluble, a person skilled in the art can thenadd a solvent B, the role of which will be to solubilize the substratein the aqueous phase.

This solvent B may be divided between the aqueous phase and the organicphase when the latter exists, either initially or with the possiblesimultaneous use of solvent A.

Preferably, water should be able to dissolve at least 1/10 of thesolvent B, more preferably at least 1/3 by weight, whether the solventis present with the catalyst and coordinating agents or not.

Preferably, solvent B is added in sufficient quantity so that thequantity of substrate soluble in the aqueous phase is at least of thesame order of magnitude as the quantity of catalyst present in theaqueous phase at the start of the reaction.

Examples of solvents B which can be used include water-soluble solventsof the following types: alcohol, nitrile, ether (especially cyclic),acid, sulfone, sulfoxide, simple or polyfunctional amides (such asurea), ester, ketone, or even amine, especially in the case where thenucleophilic compound also serves as a solvent.

As stated earlier, when the substrate and/or end product are sparinglysoluble in the aqueous phase, it is possible to carry out the reactionwith the use of solvents A and/or B. This can be accomplished, forinstance, by adding another solvent B with solvent A once solvent A isalready added or as a simultaneous addition. Alternatively, solvent Bcan be added alone, without the addition of a solvent A.

According to the present invention, the use of the term "aqueous phase"in the present invention should be understood in the broadest sense,meaning it is not necessary for there to be a high proportion of waterin addition to any solvent B, the catalytic system, and the constituentsspecified in the present description. Good results can be obtained evenwith quantities of water as low as 5% by volume, or even less than 1%.

Excellent results can even be obtained without the specific addition ofwater, because the water present in undried solvents can, in certainsituations, be sufficient.

More specifically, rather than speaking in terms of an aqueous phase ina broad sense, it would be appropriate to also refer to such an aqueousphase as a hydrophilic phase having water-like dissolving and solvatingproperties.

Thus, the present invention will not be departed from by usinghydrophilic phases (e.g., containing, as a principal constituent, asolvent or a mixture of solvent, which is miscible in all proportionsand which is itself miscible in high proportions) having the capacity todissolve a catalytic system of the type specified above and be watersoluble meaning soluble in water in a narrow sense over all or part ofthe concentration range provided for in the present invention.

As seen in the case of phenol (φ), solvent A may also be chosen so thatit also plays the role of the solvent B (or conversely). In this case,solvents are used which have a polar functional group of the typesimilar to that of solvents B having a lipophilic chain chosen such thatthe water dissolves a solvent B in an amount of about 1/100 to 1/10 byweight.

The metals which give the best catalytic results are platinum groupmetals, preferably those which are isoelectronic with palladium at avalency which is isoelectronic with palladium zero. However, it may beeconomically advantageous to use less heavy metals because of their muchlower cost. Within the family of group platinum metals, each havespecific characteristics which make them more or less advantageousdepending upon the specific reaction involved. Palladium, especiallywith the oxidation number zero, most often gives the best results.

Preferably, the ligands, also known as coordinating agents, used to formthe complex with the Group VIII element are trivalent hydrocarbonderivatives of Group VB elements. More preferably, the Group VB elementsare chosen from elements above the second row and generally below thesixth row of the periodic table of elements (supplement to the Bulletinof the Chemical Society of France, January 1966, No. 1). In addition tothose which are described in detail in the following text, examples ofsuch compounds include trivalent oxygenated acids (e.g., phosphorus,arsenious, antimonous and nitrous), and derivatives obtained especiallyby etherification or by substitution of at least two of the threehydroxyls (trisubstitution in fact results in pnictines which aredescribed in greater detail below). p Among the hydrocarbon derivativesdiscussed above, the most preferred group V elements are those which arederived from hydrogen pnictides by total or partial substitution of thehydrogen or hydrocarbon residues which may be attached to the Group VBatom by a double bond (as in imines) or a triple bond (as in nitriles).

The hydrocarbon derivatives of the Group V elements are preferablyderived from hydrogen pnictides by total or partial substitution of thehydrogen by monovalent hydrocarbon residues, such as alkyls. Thesesubstituted alkylated e.g., compounds will, by analogy with the termpnictide, be designated in the present description by the termpnictines.

Thus, in the case of nitrogen, the substitution of the hydrogen nitride(ammonia) results in amines. In the case of phosphorus, the substitutionof the hydrogen phosphide results in phosphines. In the case of arsenic,the substitution of hydrogen arsenide results in arsines. In the case ofantimony, the substitution of hydrogen antimonide (or stibide) resultsin stibines. The hydrocarbon derivatives of phosphorus such as thephosphines are most preferred.

Preferably, the catalyst includes, as the water-soluble ligand, apnictine or a trialkylphosphine, most preferably (for economic reasons)a triarylphosphine, or a triphenylphosphine. The phosphine and the GroupVIII metal are preferably in the form of tetrakis (phosphine) metal.

In order to render the ligands and especially the pnictines soluble, itis advisable to graft polar water solubilizing groups onto the ligands.

Neutral groups may be grafted such as polyols, but given the stronglipophilic nature of the pnictines, it is preferable that the graftedgroups be ionic, either cationic as the quaternary ammonium compounds,or anionic, as the groups which constitute the base associated withpreferably strong acids. In this latter case, examples includecarboxylic, sulfonic and phosphonic groups, and more generally thosegroups which give an equivalent hydrophilicity.

Such grafted groups used to modify phosphines are further described inFrench Patent Publication No. 2,366,237, which corresponds to U.S. Pat.No. 4,219,677 issued Aug. 26, 1980, or in French Patent Publication No.2,549,840, which corresponds to U.S. Pat. No. 4,654,176 issued Mar. 31,1987, which are hereby incorporated by reference.

Soluble triphenylphosphine trisulfonates P(C₆ H₄ --SO₃ ⁻)₃, for exampleof alkali metals, and those of formula P(C₆ H₄ --CO₂ H)₃, preferably inanionic form, are examples of the water-soluble phosphines.

Thus, according to a particularly advantageous embodiment of the presentinvention, a two-phase system can be used in which one of the two liquidphases is an aqueous phase in which the group VIII metal is solubilizedin an aqueous phase by a water-soluble pnictine or a similar compound.

When there are risks of poisoning the catalyst, that is to say when oneutilizes nucleophiles termed "soft" or in general where the nucleophilicfunction is based on metalloids of an heightened rank at least equal tothose of phosphorous or of sulfur, it is preferable to use either:

(a) phosphines where the basicity is raised. A weak basicity, which isfound with the triaryl phosphines increases with the number ofreplacements of aryl groups for the chains whose ultimate undesirableunsaturated bonds are not conjugated with the doublets of an element ofGroup V (like, for example, the bi- or tricyclohexylphosphines); or

(b) some polyfunctional pnictines, in general bifunctional, permitting achelation of the metal by the pnictine functions.

In general, the pnictine functions are, by taking the most direct path,separated by two, three or four atoms, usually carbon; e.g., formulas ofthe type ω, ω' diphenyl-phosphoethane or ω, ω' diphenyl-phosphinobutane.

This technique greatly facilitates the recovery and recycling of thecatalyst, which is one of the key parameters for the profitability ofthis type of process because of the ever increasing price of crudeplatinum metal.

Within the scope of the present invention, a metallic catalyst may beused in elemental form (oxidation number zero) or in oxidized form.These catalysts may be in the form of salts, oxides or complexes. Amongthe salts, oxides and complexes of the metals mentioned earlier,palladium chlorides, palladium acetate and palladium chloride complexedwith benzonitrile are examples having the oxidation number II. It shouldbe emphasized that the anions are of little importance, only the cationsmatter.

Palladium dibenzylideneacetone is an example of an metal complex havingthe oxidation number zero.

It should be emphasized that the oxidation number of the metal is notnecessarily preserved in the reaction. Indeed, the pnictines aregenerally sufficiently reductive to reduce palladium in elemental formeven when introduced in the form of palladium(II).

For a better implementation of the present invention, the amount ofcatalyst should be used such that the molar ratio of the metal catalystand the compounds of the group V elements, when these latter compoundsare in the form of ligands, is between 2 and 100, preferably from 4 to30. These molar ratios must take into account the number of coordinatefunctional groups per molecule. Thus, when molecules having two pnictinefunctional groups are used as ligands, the values for the ranges aboveshould be divided by two.

The quantity of aqueous phase used is such that the concentration of thegroup VIII metal in the solvent is preferably greater than 10⁻⁵,advantageously from 10⁻² to 10⁻³ M.

The nucleophilic compound or nucleophile should have twocharacteristics, namely, it should, on the one hand, be nucleophilic,that is to say rich in electrons, and, on the other hand, bewater-soluble.

In the present invention, preferably the nucleophiles are superior tothose of ammonia (see March, 3rd edition, p. 307-309).

In fact, the choice of nucleophile depends on the functional groups tobe deprotected. In general, molecules bearing a functional group(s)which is at least as nucleophilic as the functional groups toward whichit is necessary to be selective, are preferably used as nucleophiles.

When the reagents are suitable, according to a particularly advantageousembodiment of the present invention, the functional groups, whosealkylation is to be avoided, are protonated and a nucleophile is chosenwhich cannot be protonated under the operating conditions. On thisassumption, this is the reason for the preference above that thenucleophilic character or nucleophilicity be greater than that of theNH₄ ⁺ ion. This protonation is performed in an aqueous phase using anacid whose pKa is at least one point, preferably at least two pointsbelow the pKa of the acid associated with the nucleophilic functionalgroup which it is desired to protect. An excess of at least 10% byweight compared to the quantity required for the neutralization ispreferable.

These nucleophiles may be anions or neutral molecules. To illustrate theabundance of this category of substrate, there may be mentioned, with nolimitation being implied:

aliphatic (primary, secondary or tertiary), aromatic or heterocyclicorganic sulfides and disulfides,

thiols,

preferably secondary pnictines (e.g., amines, phosphines)

In order to be hydrophilic, or rather water-soluble, that is to saysoluble in water, the nucleophilic compound should be such that undernormal conditions, at least 0.2, advantageously 0.5, preferably 1 gramequivalent of the nucleophilic functional group is dissolvable in water.

It should be noted that nucleophilic reagents which may be insoluble orsparingly soluble in water can be rendered water-soluble by using astrongly hydrophilic functional group in the molecule. Strong or mildacid functional groups (pKa at most equal to 6, preferably equal to 5,most preferably equal to 4) whether containing sulfur (sulfonic,sulfuric and the like), phosphorus (phosphoric ester, phosphonic acid,phosphonic acid and the like), carbon, or the like, give sufficientlygood results. The best results are obtained with a carbon functionalgroup, namely the carboxylic functional group.

Advantageously, good results are obtained using nucleophiles where thenucleophilic functional group is carried by a carbon which ispostvicinal or preferably vicinal to that carrying the acid functionalgroup. Thus, one of the best nucleophiles is thiosalicylic acid(H--S--φ--COOH), especially in acidic or monoanionic form.

It is of course preferable that the water and the nucleophile should bemiscible in all proportions. Also, the same compound may carry severalnucleophilic functional groups.

It is preferable to have, relative to the number of carbons, at leastone nucleophilic functional groups per 10 carbon atoms, preferably oneper 8, most preferably one per 4.

It is also preferable to use small molecules in which the number ofcarbons is not substantially greater than about ten.

Finally, it may be convenient to choose a nucleophilic compound whosesolubility decreases substantially with increasing temperature as itpasses to the gaseous phase, thus permitting easy removal bydistillation.

In general, the nucleophilic compound is present (initially, but morepreferably at the end of the reaction) at a concentration of at least1/2, advantageously 2, preferably 5 gram equivalents per liter.

When the nucleophilic compound has a low molecular mass, expressed interms of nucleophilic functional group, concentrations as high as 10equivalents per gram are often exceeded.

When the selectivity offered by use of the aqueous phase is not judgedto be sufficient and it is desirable to increase it, it is possible, inorder to achieve this, to adjust the excess of the nucleophilic compoundrelative to the substrate. For example, this may be accomplished byincreasing the stoichiometric excess (in general substantially greaterthan 10%) relative to the desired reaction so as to bring it to a valueat least equal to 1/4, preferably 1/2, most preferably to one times thestoichiometric quantity. In other words, to work with quantities atleast equal to 5/4, 3/2 and 2/1 the stoichiometric quantity,respectively.

Preferably, the quantity of the nucleophile is at least equal to 3/2times the stoichiometric quantity required.

The objects of the present invention are also achieved, in part, bymeans of a process for treating molecules comprising at least oneunsaturated alkyloxycarbonyl functional group wherein the molecule issubjected to the reagents specified above.

Advantageously, the molecules which comprise at least onealkyloxycarbonyl functional group, correspond to the following formula(I):

    Z--O--C--(R.sub.1)(R.sub.2)--C(R.sub.3)═C(R.sub.4)(R.sub.5)(I)

where

R₁ represents a hydrogen or an alkyl radical, preferably containing 1 or2 carbon atoms;

R₂ represents a hydrogen or an alkyl radical, preferably containing 1 or2 carbon atoms;

R₃ represents a hydrogen or an alkyl radical, preferably containing 1 or2 carbon atoms or, with R₄, forms an additional double bond;

R₄ represents a hydrogen or an alkyl radical, preferably containing 1 or2 carbon atoms or, with R₃, forms an additional double bond;

R₅ represents a hydrogen or an alkyl radical, preferably containing 1 or2 carbon atoms, or an aryl radical;

Z represents an alkyl radical, including carbamyl, alkoxycarbonyl,thioalkoxycarbonyl and an equivalent compound;

Z contains the molecule protected and which should be released from itsprotecting group;

R₅ may be a group termed "Ar" as described in British Patent Applicationfiled on Dec. 31, 1990 under the No. 90 28208.8 and entitled "ProtectingGroup", which corresponds to U.S. Ser. No. 07/920,579, filed on Aug. 28,1992 and U.S. Ser. No. 08/003,698, filed on Jan. 13, 1993, which arehereby incorporated herein by reference.

R₅ and R₄ may be fractions of the group termed "Ar" in the aboveapplication so that R₅ and R₄, as well as the carbon bearing them, formsan Ar radical as defined in the above British applications.

R₅ may be any lipophilic group as disclosed in French Patent ApplicationNo. 89/13054, filed on Oct. 2, 1989 and entitled "Process forSolubilizing Peptides and Process for Synthesizing Peptides" and thatfiled on Dec. 4, 1989 under the No. 89/15057 and entitled "Reaction andSolubilizing Medium for Peptides and Process of Synthesis Using ThisMedium", which corresponds to U.S. Ser. No. 07/998,757, filed on Dec.30, 1992, which is hereby incorporated by reference.

Generally, the association of the group designated by Ar in the aboveBritish application with an allyloxycarbonyl group as the lipophilicgroup "L" is greatly favored.

Most often, Z is of the formula Z'--CO--with Z' being the radicalderived from the molecule to be protected, the bond replacing a hydrogenof the functional group which it is desired to protect.

It is preferable that Z' have the structure Z"--X, with X being an atomother than carbon, advantageously of Groups V or VI.

Z contains a number of carbons up to 3, more often up to 5 andfrequently up to 10.

The protected molecules are often amino acids, peptides, sugars andnotably some nucleotides or chains thereof.

Z' is a polyfunctional group (preferably, at least bi-, more preferably,at least tri-functional) as noted; the function being most frequentlyprotected by diverse group protectors. It is often very important thatthe cleaving of the protective function be selected with regard to theother protective functions which is the case with the reactive reagentaccording to the present invention.

Therefore, the present invention furnishes a process useful for theselective cleavage of a molecule having at least one function protectedby an allylcarbonyl protective group and having at least one functionprotected by a protective group different from the allyl carboxylprotective group. We are therefore dealing with a selection cleavageprocedure both with regard to different allyl groups and with regard tothe other protective groups.

The term alkyl is taken in its etymological sense already specified,with the additional information that it can also mean an aryl group.

It is preferable that at least 2, more preferably 3, most preferably 4,of the radicals R₁ to R₅ should consist of at most two carbons. However,at least one of the radicals R₁ to R₅ may be such that the allyl alcoholis a heavy alcohol, for example of the aromatic series, of the terpenetype or of the steroid series.

Thus, at least 1 radical and at most 3 radicals R₁ to R₅ may bepolycyclic, condensed or otherwise, homo- or heterocyclic aryl radicals.

Most surprisingly, the present invention allows the selective liberationof protected functions by allyloxy carbonyls in which the substituentsR₁ to R₅ are different. The less the allylic group is substituted, theeasier is the liberation. More precisely, the reactivity of differentallyl groups depends strongly upon the degree of substitution of theallyl group. If one designates the number of substituents on R₁ to R₅ bythe letter "p", the more p is raised, the more the sensitivity of thereactive reagents to the base palladium (zero oxidation state), or tothe other metals of Group VIII which are isoelectronic, decreases.

A monophasic medium distinguishes slightly less clearly thenonsubstituted from the monosubstituted but distinguishes easily thedisubstituted from the monosubstituted.

Finally, the efficiency of selectivity occurs according to theconcentration of the catalyst and degree of substitution of the allylgroup, making it possible to realize the extremely selective liberationof the protective groups.

This differential reactivity among the different allyl groups can leadto total selectivities by adjusting the parameters already identified.Thus, a biphasic medium favors very strongly the allyl groups that aresubstituted little or not at all.

This remarkable property permits the synthesis of complex molecules suchas peptides and polynucleotides by protecting them withallyloxycarbonyl. The present invention further permits the synthesis ofthe functions of whose liberation is desired.

Thus, the present invention permits the utilization of molecules of thestructure:

    ∫(--CO--O--allyl.sub.i).sub.n

with _(i) having all the full values of 1 to n (n≧2 or 3, n≦100 or 50),

allyl_(i) having the formula --C(R₁)(R₂ --C)(R₃)═C(R₄)(R₅), and

∫ is the rest of the polyfunctional molecule.

The allyl_(i) groups are those which have in the molecule at least two,preferably three, different formulas of allyl_(i) ; it is preferablethat these formulas present respectively 0, 1 and/or 2 of thesubstituents R₁ to R₅.

The reaction temperature is generally between the finishing meltingpoint and the starting boiling point of the reaction medium,advantageously between 0° C. and 100° C., preferably between roomtemperature (about 20° C.) and 50° C.

It is evident that the selectivity increases when the reaction iscarried out in two phases, but the kinetics, although remaininggenerally high, decreases.

The process according to the invention preserves the geometry of themolecules and is therefore particularly well suited to the chemistry ofthe chiral molecules.

The following nonlimitative examples illustrate the present invention.##EQU1##

EXAMPLES ##STR1##

About 250 mg [(n=0.0012 mol of substrate protected by the "Alloc"functional group (=allyloxycarbonyl)] were introduced into a reactor andthen dissolved in 3 ml of reaction medium (such as for example CH₃ CN).After purging and degassing with argon, the nucleophile (diethylamine)was added (2.2 eg.; n=0.0026 mol); v=0.272 ml) with stirring and underargon.

The reaction medium was then added:

6.2×10³ g (n-2.76×10⁻⁵ mol) of Pd(OAc)₂ ;

8.12×10⁻² g of an aqueous solution of sodiumTriPhenylPhosphinetriSulfonate (TPPTS) (32.5% aqueous solution; 0.505milliequivalent of phosphine/g); and

0.2 ml of water.

The reactions were monitored by gas chromatography using a column knownunder the name HPI methyl silicone-Grum having dimensions 5 m×0.53mm×2.65 and another column known under the name 8E 30, a capillarycolumn, the usual treatment, chromatography or crystallization. Thecrude reaction product was usually treated by evaporation of thesolvents after taking up in toluene, followed by a crystallization, achromatography or distillation of the crude product under reducedpressure.

The structure of the products was checked by analysis and comparisonwith a standard product(s) by ¹ H NMR, gas chromatography and ovulationof the specific rotation when chiral molecules were treated.

Yield expressed in % recovered.

DEPROTECTION OF ALCOHOLS

Reagents=Pd(OAc)₂, TPPTS at room temperature in CH₃ CN/H₂ O

    __________________________________________________________________________    Example No.                                                                         Substrate     Products Obtained                                                                       Time in min.                                                                         Yield                                                                             Nucleophile/substrate ratio          __________________________________________________________________________      1 Benzyl Benzyl 10'  90% 2,2                                                   allyloxy- alcohol                                                             carbonate                                                                    2 Cyclohexyl Cyclohexyl 10' 79% 2,2                                            methyl carbinol                                                               allyloxy-                                                                     carbonate                                                                    3 Citronellyl Citronellol  5' 94% 2,2 and 2,5                                  allyloxy-                                                                     carbonate                                                                    4 (tBu)(Φ).sub.2 Si-OCH.sub.2 -- (tBu)(Φ).sub.2 Si-OCH.sub.2 --                                              10' 98% 2,5 eq.                         *CH(OAlloc)CH.sub.2 --COOMe *CHOHCH.sub.2 CO                                   O-Me                                                                      __________________________________________________________________________                           HNET.sub.2                                                                        Time in                Yield(c)                      Examples Substrate (eq.) min. or h Product (%)                              __________________________________________________________________________       - 5                                                                                                                            5 15' #                                                                       96 R3##                      - 6                                                                                                                            5 5' ##                                                                       99 R5##                      - 7                                                                                                                            3,2 5 H                                                                       99 R7##                      - 8                                                                                                                            2 15' #                                                                       100.sup.(c)                  - 9                                                                                                                            3,2 90'                                                                       99 R11##                     - 10                                                                                                                           2,1 60'                                                                       100.sup.(c)               __________________________________________________________________________

DEPROTECTION OF ALCOHOLS

Reagents=Pd(OAc)₂, TPPTS at room temperature, two-phase

    ______________________________________                                                                               Nucleophile/                                  substrate                                                                Examples  Products Time in  ratio                                             No. Substrate Obtained min. Yield solvents                                  ______________________________________                                        11      Citronellyl                                                                            Citronellol                                                                             >12 h 51%   2,5 eq.                                   allyloxy-    Et.sub.2 O/H.sub.2 O                                             carbonate                                                                    12 Citronellyl Citronellol 3h00 76% CH.sub.2 Cl.sub.2 /H.sub.2 O                                                     allyloxy-    5 eq.                      carbonate                                                                  ______________________________________                                    

A--Deprotection of Alcohols

Study under various conditions, in a two-phase medium containingcitronellyl allyloxycarbonate.

    __________________________________________________________________________      #STR14##                                                                    Entry                                                                             Substrate            Products     Solvent                                                                            Time (h)/RT                                                                          NuH (eq)                                                                              Yield %             __________________________________________________________________________       - 13                                                                                                                                   #STR15##                                                                      CH.sub.3 CN                                                                 2,5 HCOOH 3,5                                                                 51%                 __________________________________________________________________________       -                                                                          Entry                                                                            Substrates                  Products             Time (min)                                                                          Yield (%)           __________________________________________________________________________       - 14                                                                                                                                   #STR17##                                                                       5' 94                                                                      #        - 15                                                                   #STR19##                                                                      10' 90                                                                      #        - 16                                                                   #STR21##                                                                      10' 79                                                                      #        - 17                                                                   #STR23##                                                                      10' 98                                                                      #        - 18                                                                   #STR25##                                                                      20' 99                                                                      #        - 19                                                                   #STR27##                                                                      90' 99##          __________________________________________________________________________

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₂ CH/H₂ O (6:1) at room temperature

EXAMPLE 20 Recycling of the Catalysts

    ______________________________________                                          #STR29##                                                                    Number of                                                                       estimation                                                                    for the  Number of                                                            catalytic Mass mol  Time Yield - %                                            phase (g) (10.sup.-3 M) Solvent* (RT) (TT)                                  ______________________________________                                        (1)    0,2    0,83     C.sub.3 H.sub.7 CN/H.sub.2 O                                                           30'     100%                                    (2) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.2 O 30' 100%                            (3) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 100%                            (4)  0,20 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 100%                          (5) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 98%                             (6) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 98%                             (7) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 99%                             (8) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 97%                             (9) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 96%                             (10) 0,2 0,83 C.sub.3 H.sub.7 CN/H.sub.3 O 30' 60% (40%                           after 12 h nonpro-                                                             tected)                                                                       98%                                                                    ______________________________________                                         *solvent: C.sub.3 H.sub.7 CH(3 ml), H.sub.2 O, EtzNH (2.2 eq.)(0.5 to 1       ml) degassed                                                                  Pd(OAc).sub.2 ; TPPTS (5%)                                               

DEPROTECTION OF ACIDS

Reagents: Pd(OAc)₂, TPPTS at room temperature, CH₃ CH/H₂ O

Single Phase

    ______________________________________                                                                               Nucleophile/                             Examples  Products Time in  substrate                                         No. Substrate Obtained min. Yield ratio                                     ______________________________________                                        27     Allyl 2,4- 2,4-dichloro-                                                                           10'   98%  2,2 eq                                    dichloro- benzoic acid                                                        benzoate                                                                     28 Cyclohexenyl 2,4-dichloro- 10' 95% 2,2 eq.                                  2,4-dichloro- benzoic acid                                                    benzoate                                                                     29 Allyl phenyl Phenyl acetic 15' 99% 2,2 and 2,5                              acetate acid                                                               ______________________________________                                    

DEPROTECTION OF PRIMARY AMINES

    __________________________________________________________________________      #STR30##                                                                    Reagents: Pd (OAc).sub.2, TPPTS at room temperature, CH.sub.3 CH/H.sub.2      Examples No.                                                                          Substrate Products Obtained                                                                      Time in min.                                                                         Yield                                                                            Nucleophile/substrate ratio              __________________________________________________________________________      30 N-allyloxycarbonyl Phenylalanine 10' 68 NuH 2,2 eq.                         phenylalanine                                                                31 N-allyloxycarbonyl Benzylamine  9' 72 2,2 eq.                               benzylamine                                                                  32 N-allyloxycarbonyl α  5' 85 2,2 eq.                                   α methylbenzyl                                                          methylbenzyl amine                                                           33 N-allyloxycarbonyl iodoaniline 10' 77 2,2 eq.                               3-iodoaniline                                                              __________________________________________________________________________    Entry                                                                            Substrates            Products     Time (min)                                                                          Yield (%)                         __________________________________________________________________________       - 34                                                                                                                     #STR31##                                                                      10' 70 #                           - 35                                                                                                                     #STR33##                                                                      15' 90##                        __________________________________________________________________________

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CH/H₂ O (6:1) Et₂ NH: 2.2 eq.

    __________________________________________________________________________    Entry                                                                            Substrates          Products     Time (min)                                                                          Yield (%)                           __________________________________________________________________________      36                                                                                                                      NHTR35##                                                                    .sub.2 --NH.sub.2 10' 99                                                        - 37                                                                          #STR36##                                                                       9' 72 #                             - 38                                                                                                                   #STR38##                                                                       5' 85 #                             - 39                                                                                                                   #STR40##                                                                      10' 77##                          __________________________________________________________________________

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CH/H₂) (6:1) Et₂ N 2.2 eq.

DEPROTECTION OF SECONDARY AMINES

Reagents: Pd(OAc)₂, TPPTS at room temperature

    __________________________________________________________________________    Examples No.                                                                         Substrates        Products Obtained                                                                         Time in min.                                                                         Yield  Nucleophile/substrate                                                         ratio                      __________________________________________________________________________      40 N,N'-allyloxycarbonyl methylbenzylamine N-methylbenzyl- 60 93 2,2                                                           eq.                            amine   AcOEt/H.sub.2 O                                                     41 N,N'-allyloxycarbonyl methylbenzylamine N-methylbenzyl- 15 82 2,2 et                                                        4                              amine   C.sub.3 H.sub.7 CN/H.sub.2 O                                        42 N-allyloxycarbonyl morpholine Morpholine  5 98 2,2 et 4,4 eq.                                                                     CH.sub.3                                                                CN/H.sub.2 O                 43 N-allyloxycarbonyl proline Proline 15 90 5 eq.                                  Et.sub.2 O/H.sub.2 O                                                     44 N,N'-allyloxycarbonyl tert-butyl para- tert-butyl N-p- 45 99 2,5 eq.        methoxyphenyl-glycinate methoxyphenyl-glycinate                              45 N,N'-allyloxycarbonyl M-methylbenzyl-   5' 23% 2,5 eq.                      methylbenzylamine amine  deprotection CH.sub.3 CN/H.sub.2 O                      77%                                                                           alkylation                                                                46 N,N'-allyloxycarbonyl N-methylbenzyl-  5 75% 6 eq.                          methylbenzylamine amine  deprotection CH.sub.3 CN/H.sub.2 O                      25%                                                                           alkylation                                                              __________________________________________________________________________                                                         Time/RT                                                                            NHEt.sub.2                                                                     Examples                                                                     Substrates                                                                    Products (min)                                                                (eq.)               __________________________________________________________________________      47                                                                                                                                      #STR42##                                                                      #STR43##                                                                      5STR44##                                                                    ' 2,2 ph: 3                                                                     - 48                                                                           0% 0% 5' to                                                                0° C.                                                                  2,2                    - 49                                                                                                                                   97% 3% 5'         __________________________________________________________________________                                                              40              

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CN/H₂ O (6:1)

    __________________________________________________________________________    Ex-                                                Time/                        am-   RT NHEt.sub.2                                                           ples Substrates Products (min) (eq.) Solvents                               __________________________________________________________________________      50                                                                                                                                      #STR47##                                                                      #STR48##                                                                      5STR49##                                                                    ' 2,2 Et.sub.2                                                                O/H.sub.2 O                                                                     - 51                                                                          84% 16% 5' 5                                                                Et.sub.2                                                                      O/H.sub.2 O                                                                     - 52                                                                          87% 13% 5' 8                                                                Et.sub.2                                                                      O/H.sub.2 O                                                                     - 53                                                                          97%  3% 5' 40                                                                Et.sub.2                                                                     O/H.sub.2           __________________________________________________________________________                                                              O               

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CN/H₂ O (6:1)

    __________________________________________________________________________                                             Time/RT                                                                            NHEt.sub.2                        Examples Substrates Products (min) (eq.) Solvents                           __________________________________________________________________________      54                                                                                                                              #STR53##                                                                      #STR54##                                                                      5STR55##                                                                    ' 2,2 CH.sub.3 CN/H.sub.                                                      2 O                            - 55                                                                                                                           80% 20% 5' 6 CH.sub.3                                                       CN/H.sub.2 O                   - 56                                                                                                                           67% 33% 5' 2,5                                                              CH.sub.3 CN/H.sub.2 O                                                           - 57                                                                          86% 14% 5' 6 CH.sub.3                                                       CN/H.sub.2 O                   - 58                                                                                                                           93%  7% 5' 15                                                               CH.sub.3 CN/H.sub.2         __________________________________________________________________________                                                      O                       

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CN/H₂ O (6:1)

    __________________________________________________________________________    Ex-                                                Time                                                                              NHEt.sub.2                                                                         am-   RT +                                                                   Yield                ples Substrates Products (min) (eq.) (%)                                    __________________________________________________________________________      59                                                                                                                                       #STR60##                                                                      #STR61##                                                                      15TR62##                                                                    ' HCl  1,1 99                                                                   - 60                                                                          50% 50% 15'                                                                 APTS  1,1 99                                                                    - 61                                                                           0%  0% 18 h                                                                AcOH  1,1                                                                     traces             __________________________________________________________________________

Medium: Pd(OAc)₂ /TPPTS (1:2) 5%; AcOEt/H₂ O (6:1)+HNEt₂ (2,5 eq.)

    ______________________________________                                        62  N,N'-allyloxy-                                                                           N-methyl  5'   97%      40 eq.                                    carbonyl benzylamine  deprotection CH.sub.3 CN/H.sub.2 O                      methylbenzyl-   3% alkylation                                                 amine                                                                        63 N-allyloxy- Piperidine 5' 60% NuH 2,2 eq.                                   carbonyl   deprotection CH.sub.3 CN/H.sub.2 O                                 piperdine   40%                                                                  alkylation                                                                64 N-allyloxy- Piperidine 2'30 80% 6 eq.                                       carbonyl   deprotection CH.sub.3 CN/H.sub.2 O                                 piperdine   20%                                                                  alkylation                                                              ______________________________________                                    

DEPROTECTION OF SECONDARY AMINES

Reagents: Pd(OAc)₂ /TPPTS at room temperature, Et₂ O/H₂ O

    __________________________________________________________________________                                                        Nucleophile/substrate       Examples No. Substrate Products Obtained Time in min. Yield ratio                                                               (solvent)                 __________________________________________________________________________    65     N,N'-allyloxy-carbonyl tert-butyl                                                            tert-butyl N-p-                                                                           45'     100%      2,5 eq.                      para-methoxyphenyl-glycinate methoxyphenyl-glycinate  deprotection                                                             (Et.sub.2 O/H.sub.2                                                           O)                          66 N,N'-allyloxy carbonyl methyl- N-methylbenzyl-  5' 84% deprotection                                                          5                            benzylamine amine  16% alkylation eq.Et.sub.2 O/H.sub.2 O                    67 N,N'-allyloxycarbonyl N-methylbenzyl- 20' 87% deprotection 8                                                                   methylbenzylamine                                                           amine  13% alkylation                                                         eq. Et.sub.2 O/H.sub.2                                                         O                          68 N-allyloxycarbonyl Piperidine 10' 86% deprotection 6 eq.                    piperidine   14% alkylation Et.sub.2 O/H.sub.2 O                             69 N-allyloxycarbonyl Piperidine  5' 67% deprotection 2,5                      piperidine   33% alkylation eq. Et.sub.2 O/H.sub.2 O                         70 N-allyloxycarbonyl Piperidine 10' 93% deprotection 15                       piperidine   7% alkylation eq. Et.sub.2 O/H.sub.2 O                          71 N,N'-allyloxycarbonyl N-methylbenzyl- 12' 84% deprotection 5 eq.                                                               methylbenzylamine                                                           amine  16% alkylation                                                         Et.sub.2 O/H.sub.2        __________________________________________________________________________                                                        O                         Ex-                               Time (min)                Yield                                                                          amples                                                                       Substrates                                                                    (eq) solvents                                                                 Products          __________________________________________________________________________                                                                (%)                                                                             - 72                                                                          HNEt.sub.2                                                                  5 15  THF                                                                       99 R66##           -                                                                            73                                                                                                                                        HNEt67##                                                                    .sub.2 5 60                                                                   THF                                                                             #STR68##                                                                      99 R69##           - 74                                                                                                                                     HNEt.sub.2                                                                  15 20  THF 97                                                                 3.sup.(c) 99                                                                    - 75                                                                          PbS.sup.-                                                                   Na.sup.+  2 2                                                                 h  EtOH 100                                                                   0.sup.(c) 99                                                                    - 76                                                                          #STR72##                                                                      20  THF 100                                                                 0.sup.(c) 99                                                                    -                 77                                                                                                                                        #STR74##                                                                      60  THF                                                                       100                                                                         76##      -                                                                   78                                                                              #STR77##                                                                      45  THF                                                                       100                                                                         79##      -                                                                   79                                                                              #STR80##                                                                      30  THF                                                                       100                                                                         82##      -                                                                   80                                                                              #STR83##                                                                      20  THF                                                                       100R85##        __________________________________________________________________________       -                                                                          Examples                                                                            Substrates            Time (min)                                                                          Product                Yield (%)            __________________________________________________________________________       - 81                                                                                                                                  60 R86##                                                                      100 87##              - 82                                                                                                                                  30 R88##                                                                      100 89##              - 83                                                                                                                                  15 R90##                                                                      100 91##              - 84                                                                                                                                  20 R92##                                                                      100 93##              - 85                                                                                                                                  20 R94##                                                                      100R95##           __________________________________________________________________________

Deprotection of Allyloxycarbonyl with Pd(dba)₂, dppb, 2-thiobenzoic Acid

       - Example Substrates Product Solvent Time HNET.sub.2 (eq) Yield     (%)       86      ##STR96##      ##STR97##      CH.sub.3 CN/H.sub.2      O 10' 2,2 73                         87      ##STR98##      ##STR99##      Et.sub.2 O/H.sub.2      O 45' 2,5 99       88      ##STR100##      ##STR101##      ##STR102##      CH.sub.3 CN/H.sub.2      O 5'  5' 2,2  4,4 98  97       89      ##STR103##      NH═NH CH.sub.3 CN/H.sub.2      O 5' 2,5 99       90      ##STR104##      ##STR105##      ##STR106##      AcOEt/H.sub.2      O 60' 10 99                   91      ##STR107##      93,2% 6,8% AcOEt/H.sub.2      O 90' 5 92*                              92      ##STR108##      68% 32% AcOEt/H.sub.2      O 15' 5 99  degassed                           93      ##STR109##      82% 6% C.sub.3 H.sub.7 CN/H.sub.2      O 15' 10 88                                       94      ##STR110##      93% 7% C.sub.3 H.sub.7 CN/H.sub.2      O 15' 5 99*

Medium: Pd(OAc)₂ /TPPTS (1:2) 5%; CH₃ CN/H₂ O (6:1)*Pd (OAc)₂ /TPPTS(1:2) 2,5%

EXAMPLE 95 Release of Proline

    __________________________________________________________________________    Substrate   Mass (g)                                                                           No. of mole (10.sup.-3 M)                                                               Solvent                                                                            Time (RT)                                                                           HNET.sub.2 (eq)                                                                     % Pd                              __________________________________________________________________________                                                  0,25  0,25  0,25  0,25                                                      0,25  0,25  0,25 1,25  2,5                                                    3,76  5,02  6,3  7,5  8,8                                                     .sub.2 O/H.sub.2 O  Et.sub.2                                                  O/H.sub.2 O  Et.sub.2                                                         O/H.sub.2 O  Et.sub.2                                                         O/H.sub.2 O  Et.sub.2                                                         O/H.sub.2 O  - # Et.sub.2                                                     O/H.sub.2 O  Et.sub.2                                                         O/H.sub.2 O 15'  15'  15'                                                     30'  60'  60' 40  2,2  2,2                                                    2,2   2,2   2,2   2,2   2,2                                                   3,26  1,63  1,088  0,88  0,65                                                  0,55  0,46                       __________________________________________________________________________

Medium: Pd(OAc)₂ /TPPTS (1:2); CH₃ CN/H₂ O (6:1).

0.9 g of L-proline (7.89×10⁻³ M) is obtained, equivalent to a yield of90% for the 7 additions

EXAMPLE 96 Various Trials

    __________________________________________________________________________    Substrate       Nucleophile                                                                         Solvent                                                                            Products Obtained   Duration                                                                           Temperature                                                                         Yield               __________________________________________________________________________                                                                HNEt112##                                                                   .sub.2  5 eq                                                                  AcOEt/  H.sub.2                                                               O                                                                               #STR113##                                                                     15' R.T. 100%        -                                                                                                                                      HNEt.sub.2                                                                  10 eq AcOEt/                                                                  H.sub.2 O                                                                       100% 30' R.T.                                                               100%                   -                                                                                                                                      HNEt.sub.2  5                                                               eq CH.sub.3 CN/                                                                H.sub.2 O   3                                                                days  4 days                                                                  R.T.  R.T.  75%                                                                 90%                  -                                                                                                                                      HNEt.sub.2  5                                                               eq CH.sub.3 CN/                                                                H.sub.2 O                                                                    15' 50°                                                                C. 100%                                                                         -                                                                             HNEt119##                                                                   .sub.2  5 eq                                                                  AcOEt/  H.sub.2                                                               O no  deprotecti                                                              on  R.T. <10%                                                                   -                                                                             HNEt.sub.2  5                                                               eq CH.sub.3 CN/                                                                H.sub.2 O  40'                                                               25° C.                                                                 100%                   -                                                                                                                                      HNEt.sub.2  5                                                               eq AcOEt/                                                                     H.sub.2 O                                                                     practically  no                                                                deprotection                                                                 25° C.                                                                 <10%                __________________________________________________________________________     Pd(o): Pd(AOc).sub.2 /TPPTS (1:2) 5 mole %                                    *solvent degassed                                                        

Conclusion

The best nucleophile for the deprotections in aqueous medium was HNEt₂.Furthermore, diethylamine was very volatile and was therefore veryeasily removed from the reaction medium. When the protecting group wasmore hindered, raising the temperature was helpful. For the deprotectionof carboxylic acids, the homogeneous medium gave good results.

EXAMPLE 97 Application to the Peptide Synthesis ##STR122## Products:studied in 'H; C¹³ ; DEPTS; Mass;

    __________________________________________________________________________    Substrate            Nucleophile                                                                          Solvent*                                                                            Products obtained                                                                           Duration                                                                            Temperature                                                                         Yield             __________________________________________________________________________                                                                  HNEt.sub.2                                                                  5 eq CH.sub.3                                                                 CN/  H.sub.2                                                                  O                                                                               15' R.T.        __________________________________________________________________________                                                                99%                  -                                                                                                             #STR125##                                                                     #STR126##                                     -                                                                          Catalyst        Et.sub.2 NH                                                                              Solvent        Time/RT    Yield                    __________________________________________________________________________      Pd(O) + DPPE: 1% 2,2 eq EtOH 6 h 62%                                          Pd(O) + TPPTS: 1% 2,2 eq CH.sub.3 CN/H.sub.2 O 15' 54%                      __________________________________________________________________________       -                                                                                                                         #STR127##                                                                    ##STR128##                      __________________________________________________________________________

We claim:
 1. A reagent for the selective cleavage of a protecting group having at least one unsaturated alkyloxycarbonyl group from a functional group having greater than 5 carbon atoms that it protects, which comprises:a) an aqueous phase; b) a catalyst comprising at least one group VIII element in the periodic table of elements and at least one water-soluble ligand, wherein said group VIII element is maintained in said aqueous phase by the formation of a complex with said at least one water-soluble ligand; and c) a nucleophilic compound soluble in said aqueous phase; wherein said unsaturated alkyloxycarbonyl group is unsaturated in the beta-position, said nucleophilic compound has a nucleophilicity equal to or greater than an NH₄ ⁺ ion, and said ligand has a solubility minimum of 2×10⁻⁵ M when monofunctional and a solubility minimum of 10⁻⁵ M when difunctional.
 2. A reagent as claimed in claim 1, wherein said water-soluble ligand is a trivalent hydrocarbon derivative of an element selected from nitrogen, phosphorous, arsenic and antimony.
 3. A reagent as claimed in claim 1, wherein said water-soluble ligand is a trialkylphosphine or triarylphosphine.
 4. A reagent as claimed in claim 1, wherein at least 0.2 equivalent per liter of said nucleophilic compound is soluble in water.
 5. A reagent as claimed in claim 4, wherein at least 0.5 equivalent per liter of said nucleophilic compound is soluble in water.
 6. A reagent as claimed in claim 5, wherein at least 1 equivalent per liter of said nucleophilic compound is soluble in water.
 7. A reagent as claimed in claim 1, wherein said nucleophilic compound is present at a concentration of at least 1/2 equivalent per liter of said reagent.
 8. A reagent as claimed in claim 7, wherein said nucleophilic compound is present at a concentration of at least 2 equivalents per liter of said reagent.
 9. A reagent as claimed in claim 8, wherein said nucleophilic compound is present at a concentration of at least 5 equivalents per liter of said reagent.
 10. A reagent as claimed in claim 1 further comprising at least one solvent.
 11. A reagent as claimed in claim 2, wherein said Group VIII element is platinum or palladium.
 12. A reagent as claimed in claim 2, wherein said derivative includes a phosphine, arsine, stibine, or an amine group.
 13. A reagent as claimed in claim 3, wherein said water-soluble ligand is triphenylphosphine.
 14. A reagent as claimed in claim 1, wherein said catalyst is in the form of a salt, oxide or complex.
 15. A reagent as claimed in claim 1, wherein said catalyst is a palladium chloride, palladium acetate, a palladium chloride complexed with benzonitrile, or a palladium dibenzylideneacetone.
 16. A reagent as claimed in claim 2, wherein the molar ratio of said catalyst and said ligand is between 2 and
 100. 17. A reagent as claimed in claim 10, wherein the quantity of said aqueous phase is such that the concentration of said group VIII element in said solvent is greater than 10⁻⁵ M.
 18. A reagent as claimed in claim 1, wherein said nucleophilic compound includes a sulfide, disulfide, thiol, or trivalent hydrocarbon derivative of an element selected from nitrogen, phosphorous, arsenic and antimony.
 19. The reagent as claimed in claim 1, wherein the amount of said nucleophilic compound is at least equal to 3/2 times the stoichiometric quantity required.
 20. A reagent for the selective cleavage of a protecting group having at least one unsaturated alkyloxycarbonyl group from a functional group that it protects, which comprises:a) an aqueous phase; b) a catalyst comprising at least one group VIII element in the periodic table of elements and at least one water-soluble ligand, wherein said group VIII element is maintained in said aqueous phase by the formation of a complex with said at least one water-soluble ligand; c) a nucleophilic compound soluble in said aqueous phase; and d) an organic phase; wherein said unsaturated alkyloxycarbonyl group is unsaturated in the beta-position, said nucleophilic compound has a nucleophilicity equal to or greater than an NH₄ ⁺ ion, and said ligand has a solubility minimum of 2×10⁻⁵ M when monofunctional and a solubility minimum of 10⁻⁵ M when difunctional.
 21. A reagent as claimed in claim 20, wherein said organic phase is a solvent A.
 22. A reagent as claimed in claim 1, wherein said functional group having said protecting group has the formula:

    Z--O--C--(R.sub.1)(R.sub.2)--C(R.sub.3)═C(R.sub.4)(R.sub.3)(I)

wherein R₁ represents a hydrogen or an alkyl radical; R₂ represents a hydrogen or an alkyl radical; R₃ represents a hydrogen or an alkyl radical or forms an additional double bond with R₄ ; R₄ represents a hydrogen or an alkyl radical or forms an additional double bond with R₃ ; R₅ represents a hydrogen or an alkyl radical; and Z represents an alkyl radical.
 23. A reagent as claimed in claim 1, wherein said functional group has greater than 10 carbon atoms.
 24. A reagent as claimed in claim 19, wherein said nucleophilic compound is an aliphatic, aromatic, or heterocyclic sulfide or disulfide, or a secondary trivalent hydrocarbon derivative of an element selected from nitrogen, phosphorus, arsenic and antimony.
 25. A reagent as claimed in claim 1, wherein said nucleophilic compound has a hydrophilic functional group.
 26. A reagent as claimed in claim 25, wherein said hydrophilic functional group is an acid functional group having a pKa of 6 or less.
 27. A reagent as claimed in claim 26, wherein said nucleophilic compound has a nucleophilic functional group carried by a carbon vicinal to said acid functional group or by the carbon following said vicinal carbon.
 28. A reagent as claimed in claim 1, wherein said nucleophilic compound is thiosalicyclic acid.
 29. A reagent as claimed in claim 1, wherein said nucleophilic compound has at least one nucleophilic functional group per 10 carbon atoms.
 30. A reagent as claimed in claim 29, wherein said nucleophilic compound has at least one nucleophilic functional group per 8 carbon atoms.
 31. A reagent as claimed in claim 30, wherein said nucleophilic compound has at least one nucleophilic functional group per 4 carbon atoms.
 32. A reagent as claimed in claim 22, wherein Z is represented by the formula:

    Z'--CO--,

wherein Z' is a radical derived from said functional group having greater than 5 carbon atoms.
 33. A reagent as claimed in claim 32, wherein Z' is represented by the formula:

    Z"--X,

wherein X is a Group V or VI atom.
 34. A reagent as claimed in claim 32, wherein Z' is a polyfunctional group.
 35. A reagent as claimed in claim 1, wherein said functional group is an amino acid.
 36. A reagent as claimed in claim 1, wherein said functional group having said protecting group is represented by the formula:

    ∫(--CO--O--allyl.sub.i).sub.n

wherein i is an integer of from 1 to 100; n is an integer of from 2 to 100; allyl, which can be the same or different when n is 2 or greater, is represented by the formula

    --C(R.sub.1)(R.sub.2 --C)(R.sub.3)═C(R.sub.4)(R.sub.5)

wherein R₁ represents a hydrogen or an alkyl radical; R₂ represents a hydrogen or an alkyl radical; R₃ represents a hydrogen or an alkyl radical or forms an additional double bond with R₄ ; R₄ represents a hydrogen or an alkyl radical or forms an additional double bond with R₃ ; and R₅ represents a hydrogen or an alkyl radical; and ∫ is a polyfunctional molecule.
 37. A reagent as claimed in claim 36, wherein i is at least 2 and said allyls are different.
 38. A reagent as claimed in claim 37, wherein i is at least
 3. 39. A reagent as claimed in claim 22, wherein R₁ to R₅ are all different from each other.
 40. A reagent as claimed in claim 1, wherein said functional group is a chiral group.
 41. A reagent as claimed in claim 17, wherein said concentration of said group VIII element in said solvent is from 10⁻² to 10⁻³ M.
 42. A reagent as claimed in claim 1, wherein said reagent is multiphasic.
 43. A reagent as claimed in claim 1, wherein said reagent is biphasic.
 44. A reagent as claimed in claim 11, wherein said solvent is a hydrophobic organic solvent which dissolves at least 1% by weight of said functional group having said protecting group.
 45. A reagent as claimed in claim 44, wherein said hydrophobic organic solvent dissolves 5% by weight of said functional group having said protecting group.
 46. A reagent as claimed in claim 44, wherein at most 10% by weight of water is dissolvable in said hydrophobic organic solvent.
 47. A reagent as claimed in claim 44, wherein at most 10% by weight of said hydrophobic organic solvent is dissolvable in water.
 48. A reagent as claimed in claim 10, wherein said solvent is a hydrocarbon, an aromatic derivative, an ether, an ester, or a halogenated solvent.
 49. A reagent as claimed in claim 11, further comprising a second solvent.
 50. A reagent as claimed in claim 49, wherein at least 1/10 by weight of said second solvent is dissolvable in water.
 51. A reagent as claimed in claim 50, wherein at least 1/3 by weight of said second solvent is dissolvable in water.
 52. A reagent as claimed in claim 49, wherein said second solvent is a water-soluble alcohol, a water-soluble nitride, a water soluble ether, a water-soluble acid, a water-soluble sulfone, a water-soluble sulfoxide, a water-soluble amide, a water-soluble ester, a water-soluble ketone, or a water-soluble amine.
 53. A reagent as claimed in claim 1, wherein said group VIII element is a platinum metal.
 54. A reagent as claimed in claim 53, wherein said platinum metal is isoelectronic with palladium.
 55. A reagent as claimed in claim 1, wherein said group VIII element is palladium.
 56. A reagent as claimed in claim 55, wherein said palladium has an oxidization number of zero.
 57. A reagent as claimed in claim 1, wherein said ligand is a phosphine.
 58. A reagent as claimed in claim 57, wherein said phosphine has increased basicity.
 59. A reagent as claimed in claim 1, wherein a polar water solubilizing group is attached to said ligand.
 60. A reagent as claimed in claim 13, wherein said triarylphosphine is triphenylphosphine.
 61. A reagent as claimed in claim 1, wherein the functional group is an acid, alcohol, amine or thiol functional group. 